Document Detail


Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy.
MedLine Citation:
PMID:  17283277     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. METHODS AND RESULTS: Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. CONCLUSIONS: Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.
Authors:
Nikolaos G Frangogiannis; Oliver Dewald; Ying Xia; Guofeng Ren; Sandra Haudek; Thorsten Leucker; Daniela Kraemer; George Taffet; Barrett J Rollins; Mark L Entman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  115     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-02-06     Completed Date:  2007-03-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  584-92     Citation Subset:  AIM; IM    
Affiliation:
Section of Cardiovascular Sciences, and DeBakey Heart Center, the Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. ngf@bcm.tmc.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Chemokine CCL2 / deficiency,  genetics,  physiology*
Female
Fibrosis
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Ischemia / etiology*,  genetics,  pathology*
Myocardial Reperfusion Injury / etiology*,  genetics,  pathology*
Myocytes, Cardiac / pathology,  physiology
Receptors, CCR2
Receptors, Chemokine / physiology*
Grant Support
ID/Acronym/Agency:
P01 HL-42550/HL/NHLBI NIH HHS; R01 HL-76246/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Ccr2 protein, mouse; 0/Chemokine CCL2; 0/Receptors, CCR2; 0/Receptors, Chemokine

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